Crucial role of Plexin C1 for pulmonary inflammation and survival during lung injury

Abstract

Acute pulmonary inflammation during lung injury is initiated by the migration of neutrophils into the alveolar space. The severity of these inflammatory changes within the pulmonary tissue determines the severity of lung injury and ultimately patient outcome. Recent work has demonstrated that the guidance protein Semaphorin 7A propagates the infiltration of neutrophils into an hypoxic tissue site, yet the role of its target receptor Plexin C1 (PLXNC1) during lung injury is to date unknown. We demonstrate here that PLXNC1(+) neutrophils are present within the alveolar space and that PLXNC1 is induced in vitro and in vivo during lung injury. In a model of high-pressure ventilation PLXNC1(-/-) animals show decreased signs of alveolar inflammation and improved survival compared with wild-type controls. Studies employing chimeric animals identified the hematopoietic expression of PLXNC1 to be of crucial importance for the observed results. Functional inhibition of PLXNC1 resulted in improved survival and ameliorated the signs of inflammation within the lung. Furthermore, the injection of a peptide binding to PLXNC1 resulted in improved survival and attenuated pulmonary inflammation. As such we demonstrate here, that previously unknown PLXNC1 holds significant importance for degree of pulmonary inflammation and determines outcome during experimental lung injury.

IL-3 Maintains Activation of the p90S6K/RPS6 Pathway and Increases Translation in Human Eosinophils

“…We found previously that IL-3-activated eosinophils adhere to plexin-C1 (15), which only known ligand is semaphorin-7A (60). Via an interaction with plexin-C1, semaphorin-7A could be involved in eosinophil migration as demonstrated for neutrophils (61). In addition, beyond semaphorin-7A, a potential translational increase of a variety of cytokines, chemokines and growth factors by eosinophils would have a strong immunomodulatory impact during an allergic disease (Reviewed in (62)).…”

New “Guidance” for the Treatment of Hepatic Ischemia Reperfusion Injury Through Semaphorins and Plexins*

“…For example, Morote-Garcia et al found that less neutrophils crossed the endothelial barrier during hypoxia in studies using Sema7a-deficient mice (7). Similar, in a study on Plexin C1, the Sema7A receptor, Granja et al found that Plexin C1 deficient mice had decreased alveolar inflammation and improved survival in a murine model for acute lung injury (8). In another study, Suzuki and colleagues evaluated the role of Sema7A in contact hypersensitivity and experimental autoimmune encephalomyelitis using Sema7A deficient mice (10).…”

“…Before the current work by König et al, other investigators presented evidence for the Sema7A signaling pathway as potent pro-inflammatory pathway during hypoxia (7), acute lung injury (8), peritonitis (9), contact hypersensitivity and experimental autoimmune encephalomyelitis (10). For example, Morote-Garcia et al found that less neutrophils crossed the endothelial barrier during hypoxia in studies using Sema7a-deficient mice (7).…”

Immunomodulatory Functions of Neuronal Guidance Proteins

“…Subsequent work showed that Sema7A is expressed on the surface of endothelial cells and increases the infiltration of neutrophils during tissue hypoxia [37]. This is likely mediated, at least in part, through the Plexin C1 receptor ( Figure [ Plexin C1 itself propagates the infiltration of immune cells into sites of sterile pulmonary inflammation and also during Zymosan A-induced inflammation [38,39]. By contrast, Sema7A was also found to be protective during dextran sulfate sodium (DSS)-induced colitis, where it increased the production of the anti-inflammatory cytokine IL-10 through the anb1 integrin receptor [40].…”